Variant: NM_016239.4(MYO15A):c.1111C>A (p.Pro371Thr)

CA8423023

423766 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: c10734bd-038d-455b-87da-5aa88d185437

HGVS expressions

NM_016239.4:c.1111C>A
NM_016239.4(MYO15A):c.1111C>A (p.Pro371Thr)
NC_000017.11:g.18119911C>A
CM000679.2:g.18119911C>A
NC_000017.10:g.18023225C>A
CM000679.1:g.18023225C>A
NC_000017.9:g.17963950C>A
NG_011634.1:g.16206C>A
NG_011634.2:g.16206C>A
ENST00000647165.2:c.1111C>A
ENST00000205890.9:c.1111C>A
ENST00000583079.1:n.744C>A
ENST00000615845.4:c.1111C>A
NM_016239.3:c.1111C>A

Likely Benign

• Met criteria codes: BS1_Supporting BP4

• Not Met criteria codes: BS2 PM3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1111C>A (p.Pro371Thr) variant in MYO15A was present in 0.208% (lower bound of the 95% CI of 295/128,454) of non-Finnish European alleles in gnomAD v2.1, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Conservation analyses suggest that this variant may not impact the protein (BP4). In summary, the p.Pro371Thr variant in MYO15A variant meets criteria to be considered likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4.

Met criteria codes

• BS1_Supporting: Present in 0.2297% (295/128,454) of non-Finnish European alleles in gnomAD v2 (lower bound of 95% CI = 0.2081%). Present in 0.2602% (177/68,012) of non-Finnish European alleles in gnomAD v3.
• BP4: REVEL 0.147. Not predicted to impact splicing. Thr is present in 1 animal (alligator) in the UCSC database. 10 other animals had different changes.

Not Met criteria codes

• BS2: This variant was seen in the homozygous state in 1 reportedly healthy adult, however the reason for genetic testing was not a diagnosis of hearing loss, so there was no information on their hearing (GeneDx internal data, ClinVar SCV000573503.3). This variant has also been observed in the heterozygous state in individuals with hearing loss without a second variant in MYO15A (PMID: 29309402, GeneDx internal data ClinVar SCV000573503.3, CeGaT Praxis fuer Humangenetik Tuebingen internal data ClinVar SCV001246433.4).
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-05-13

Published on: 2022-05-13